Opening of Mitochondrial K ATP Channels Triggers Cardioprotection

Ischemic preconditioning, a phenomenon in which brief episodes of ischemia and reperfusion paradoxically protect the heart against subsequent lethal ischemia,1 has been conceptually divided into triggers and mediators/effectors.2 3 The trigger, which acts before the index ischemia, is followed by the protection of mediators/effectors during the lethal ischemia. Known triggers include activation of adenosine receptors, α1-adrenegic receptors and opioid receptors, elevated intracellular Ca2+, and increased reactive oxygen species (ROS).2 The mitochondrial ATP-dependent potassium channel (mitoKATP) has been proposed to be the mediator of this protection.4 The link between the trigger and effector may be the activation of protein kinases (eg, protein kinase C, tyrosine kinase, and downstream kinases), which may phosphorylate mitoKATP, causing the channel to open early and/or to a greater extent to reduce injury during the lethal ischemia. Interestingly, opening of mitoKATP can also trigger cardioprotection. Hearts treated with the mitoKATP opener diazoxide for a brief period before ischemia had significantly smaller infarction.3 5 The triggering effect from diazoxide can be blocked by protein kinase C5 6 and tyrosine kinase inhibitors,3 suggesting that diazoxide activates protein kinases, acting similarly to other triggers. This effect was lost when ROS scavengers were coadministrated with diazoxide.3 ROS are known to activate protein kinases and act as a trigger.2 Thus, it was proposed by Pain et al3 that the opening of mitoKATP by diazoxide may increase ROS.In this issue of Circulation Research , Forbes et al7 provide a direct demonstration that opening of mitoKATP increases ROS production in isolated rat ventricular myocytes. Using a ROS-sensitive fluorescent probe 2′,7′-dichlorofluorescin (DCF), they showed that diazoxide as well as pinacidil (a nonselective KATP opener) increased DCF fluorescence, implying an elevated ROS …